Expression of the growth-promoting integrin ανβ6 in colon cancer cells induces gelatinase B secretion and activation, the inhibition of which abolishes ανβ6-mediated tumour cell growth within a collagen matrix. Herein, we show that high cell density selectively enhances ανβ6 expression in a protein kinase C (PKC)-dependent manner in preference to other integrin subunits, resulting in a marked increase in gelatinase B secretion as cells reach confluence. Moreover, PKC activity increases with cell confluence, and the rise in PKC activity is much greater for ανβ6-expressing cells than for colon cancer cells which lack ανβ6. We propose a self-perpetuating system of colon cancer progression in which the integrin ανβ6 provides a means of sustaining tumour cell proliferation. In this model, ανβ6 regulates its own expression via a PKC-mediated signalling pathway as tumour cells become crowded and quiescent. The ανβ6-mediated induction of gelatinase B secretion facilitates peri-cellular matrix degradation, which helps overcome crowding and restores cell proliferation.